Prolonged exposure to hyperoxia causes tissue damage in many organs and tissues. Since the entire surface area of lung epithelium is directly exposed to O2 and other inhaled agents, hyperoxia leads to the development of both acute and chronic lung injuries. These pathologic changes in the lung can also be seen in acute lung injury (ALI) in response to other agents. Simple strategies to mitigate hyperoxia-induced ALI might not be effective by virtue of merely reducing or augmenting the extent of apoptosis of pulmonary cells. Identification of the specific cell types undergoing apoptosis and further understanding of the precise timing of the onset of apoptosis may be necessary in order to gain a greater understanding of the connection between apoptosis and tolerance to hyperoxia and ALI. Attention should also be focused on other forms of non-apoptotic programmed cell death.